A one-pot septanoside formation and glycosylation of acyclic dithioacetals derived from 1,2-cyclopropanated sugars

Article abstract of DOI:10.1039/c3cc49116a

Ring opening of 3-oxo-1,2-cyclopropanated sugars with thiols leads to the serendipitous discovery of the synthesis of sugar based homologated acyclic dithioacetals. These acyclic dithioacetals were found to undergo one-pot septanoside formation followed by stereoselective glycosylation in the presence of glycosyl acceptors under glycosylation reaction conditions. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc49116a

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A one-pot septanoside formation and
glycosylation of acyclic dithioacetals
derived from 1,2-cyclopropanated sugars†
Cite this: Chem. Commun., 2014,
50, 2218
Received 29th November 2013,
Accepted 24th December 2013
Patteti Venukumar, Chalapala Sudharani and Perali Ramu Sridhar*
DOI: 10.1039/c3cc49116a
www.rsc.org/chemcomm
Ring opening of 3-oxo-1,2-cyclopropanated sugars with thiols
In continuation of our efforts in developing general protocols
leads to the serendipitous discovery of the synthesis of sugar based for the preparation of septanoses and septano-oligosaccharides,8f
homologated acyclic dithioacetals. These acyclic dithioacetals were we attempted to prepare the septanoside derived thio-glycoside
found to undergo one-pot septanoside formation followed by donors8d from 3-oxo-1,2-cyclopropanated pyranose derivatives.8f
stereoselective glycosylation in the presence of glycosyl acceptors However, this effort led us to the serendipitous discovery of a
under glycosylation reaction conditions.
novel method to synthesize heptanose derived dithioacetals from
1,2-cyclopropanated sugars. Previously, the dithioacetal derivative
Ring expanded versions of hexoses, commonly known as septanoses of glucose has been converted to D-glucoseptanose in low yield.9
or carbohydrate based oxepanes, drew special interest in recent years Later, Hindsgaul et al. used appropriately protected O,S-acetal as a
due to their significant application as mimics of the natural glycans, precursor for the synthesis of septanoside derivatives.8c These
like furanoses and pyranoses.1 Kuszmann et al. revealed that observations prompted us to use the obtained dithioacetals as
septanose mimics of thio-pyranose exhibited a 10 fold increase in glycosyl donors in septanoside synthesis. Thus, herein we report
activity with reference to beciparcil, an oral anti-thrombotic drug.2 the synthesis of carbohydrate based dithioacetal donors from
Similarly, the methyl b-septanoside mimic of a-mannopyranoside 3-oxo-1,2-cyclopropanated pyranoses as well as a one-pot intra-
was found to be a competitive ligand for concanavalin A, a natural molecular acetal exchange, followed by glycosylation to afford
lectin for a-mannosides.3 Damha et al. synthesized septanose the septanoside containing disaccharides.
mimics of DNA and RNA by replacing the pentofuranose ring in
Towards the synthesis of thio-septanoside donors, 3-oxo-1,2-
natural nucleic acids with cyclic seven-membered sugar units. These cyclopropanated sugar 1 was reacted with thiophenol (1.2 equiv.) in
oxepane nucleic acids are found to be highly resistant to nuclease the presence of TMSOTf (0.2 equiv.) to obtain the 4-oxo-septanose
degradation while displaying several common features with the donor 2. However, the reaction provided the dithioacetal derivative
naturally occurring DNA.4 Septanose mimics of nucleosides were 3 as the only product in 52% yield and no trace amount of 2 was
also found to possess excellent anti-viral properties.5 As a result, observed. Increasing the equivalents of thiophenol (2.2 equiv.)
several protocols for the preparation of septanoses were developed in provided 3 in 98% yield (Scheme 1).
the last decade.6 The majority of septanosides synthesized to date
Performing the reaction in the presence of EtSH or TolSH
lack the substituent at the C-6 position. Furthermore, stereoselective provided the corresponding dithioacetals 4 and 5, respectively,
synthesis of septanoses containing di- and oligosaccharides is still in excellent yield. To investigate the generality of the reaction,
in the course of investigation. Recently several methods for the 3-oxo-1,2-cyclopropanated galactose derivative 6 was reacted
synthesis of septanoses have been reported.7 However, very few proto- with PhSH or EtSH or TolSH. In all cases the reaction
cols were revealed for the synthesis of septano-oligosaccharides.8 provided the corresponding dithioacetals 7, 8 and 9 in excellent
Out of these, glycosylation of 1,2-anhydroseptanosides,8b
S-phenyl septanosides8d and 1,2-cyclopropanated sugars8f as
glycosyl donors with sugar derived glycosyl acceptors was found
to be the promising technology.
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India.
Scheme 1 Formation of acyclic dithioacetal derivatives from 3-oxo-1,2-
cyclopropanated sugar. Reagents and conditions: (a) PhSH, TMSOTf,
CH2Cl2, ꢀ10 1C, 30 min, 98%.
E-mail: p_ramu_sridhar@uohyd.ac.in; Fax: +91 4023012460; Tel: +91 4066794823
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc49116a
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Scheme 2 Formation of acyclic dithioacetal derivatives from 3-oxo-1,2-
cyclopropanated sugars. Reagents and conditions: (a) RSH, TMSOTf,
CH2Cl2, ꢀ10 1C, 30 min.
yield (Scheme 2). Although the formation of thioglycosides from
1,2-cyclopropanated hexoses is known,10 to the best of our knowledge,
this is the first report on the formation of heptanosyl dithioacetals
from 1,2-cyclopropanated donor–acceptor cyclopropanes.
We further investigated whether the obtained dithioacetal 3
can be converted to the expected thioglycoside 2 in the presence
of an electrophile. Thus, dithioacetal 3 was treated with N-iodo-
succinimide (NIS)11 and catalytic AgOTf in CH2Cl2 in the presence
of 4 Å molecular sieves at ꢀ10 1C. However, this reaction also did
not provide the expected thioseptanoside 2. Interestingly, when the
reaction was performed in the presence of a glycosyl acceptor 10, it
produced the disaccharide 11 along with the bridged bicyclic
glycoside 12 in a 2 : 3 ratio,12 respectively (Scheme 3).13
The formation of 12 can be speculated by the interesting
intramolecular septanoside formation followed by the glycosyla-
tion reaction. As shown in Scheme 4, activation of the dithioacetal
3 with NIS would provide the septanosyl donor 2 by an intra-
molecular 7-exo-tet cyclisation reaction. Further activation of the
thioglycosyl donor 2 in the presence of NIS or phenylsulfenyl
iodide would lead to the formation of an oxonium ion inter-
mediate 2a that would be trapped by triflate (in the presence of
silver triflate) and undergo glycosylation in the presence of the
acceptor 10 to give the septano-hexoses 11a and 11b. On the
other hand, trapping of the oxonium ion 2a by carbonyl oxygen
in an intramolecular fashion would lead to the formation of a
tertiary carbocation intermediate 2b which upon reaction with
Scheme 4 Proposed mechanism for the formation of septano-hexose
disaccharide derivatives 11 and 12 from dithioacetal 3.
glycosyl acceptor 10 would give the unexpected disaccharide
derivative 12 as a single diastereomer. Carrying out the reaction
in the absence of AgOTf also provided disaccharide derivatives
Scheme 3 One-pot septanoside formation and glycosylation reaction of
sugar derived acyclic dithioacetal donors. Reagents and conditions: (a) NIS,
AgOTf, CH2Cl2, 4 Å MS, ꢀ45 1C to ꢀ25 1C, 1 h, 71% (11 : 12 (2 : 3)).
Scheme 5 One-pot synthesis of septano-hexoses. Reagents and condi-
tions: (a) NIS, AgOTf, CH2Cl2, 4 Å MS, ꢀ45 1C to ꢀ25 1C, 1 h.
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Table
1
One-pot synthesis of septano-hexoses from sugar derived
26 (Table 1, entries 3–6) respectively as single anomers with
a-configuration.14 The stereochemistry at the newly formed
acyclic dithioacetal donors
glycosidic center for all the septano-hexoses was assigned based
Dithioacetal
donor
Glycosyl
acceptor
Septano-hexose
derivativesa (%)
13
on the C chemical shift value of C10 (for a-septanosides dC1
0
Entry
1
0
ranges from 99–104 ppm while for b-septanosides dC1 ranges
from 104–111 ppm).15 The stereoselectivity of the glycosylation
reaction as well as the vanishing of bridged bicyclic compounds
(Table 1) may be due to the combination of stereoelectronic
effects of the seven membered oxocarbenium ion intermediate
(similar to 2a) and non-bonding steric interactions of glycosyl
acceptors.16 To the best of our knowledge, this is the first report
on use of the acyclic dithioacetals as glycosyl donors in glyco-
sylation reactions.
In conclusion, preparation of heptanose derived dithioacetals
from 1,2-cyclopropanated sugars was discovered. Furthermore, an
interesting one-pot intramolecular cyclization of acyclic dithio-
acetals to give septanosides followed by glycosylation, in the
presence of a glycosyl acceptor, to provide septano-hexoses, is
revealed. A possible mechanism for the one-pot reaction is proposed
and the generality and stereoselectivity of the glycosylation
reaction have been investigated. The application of these
dithioacetals in oligosaccharide synthesis and preparation of
carbohydrate mimics is in progress.
7
7
13
2
3
16
3
3
4
5
Notes and references
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a
Yield refers to pure and isolated products.
11 and 12 in a prolonged period of time, 48 h, in low yield
(Scheme 4).
Encouraged by this result the glycosylation reaction was
performed by using dithioacetal donor 3 and sugar acceptors
13 and 16 possessing a primary hydroxyl group as a nucleophile.
In both cases the reaction proceeded smoothly and provided the
septano-hexoses 15 and 18 as a mixture of anomers, respectively,
in low yield. However, the formation of bridged bicyclic glyco-
sides 14 and 17 was also observed under these glycosylation
reaction conditions (Scheme 5).
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galactose based dithioacetal donor 7 and acceptors 13 and 16
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